Preformulation of FK506 Prodrugs for Improving Solubility

Abstract

In order to improve water solubility of a lipophilic drug, tacrolimus (FK506), two prodrugs (FK506-G or FK506-S) such as FK506-M32-LS-G (FK506-G) and FK506-M32-LS-SL (FK506-S) were synthesized. Two prodrugs (FK506-G or FK506-S), including FK506, were characterized by differential scanning calorimetry (DSC), X-ray diffractometry (XRD), scanning electron microscopy (SEM), enzymatic kinetics, and cytotoxicity. A phase solubility test was conducted in distilled water, and the solubility of two prodrugs (FK506-G or FK506-S) was measured in various pH values for pH solubility profiles. Most interesting was that FK506-S showed the highest solubility, 866 μg/mL in water. In vitro enzymatic kinetics of two prodrugs (FK506-G or FK506-S) in human plasma was evaluated by measuring the decrease of FK506-G or FK506-S as well as the increase of FK506 by HPLC, and FK506-G or FK506-S was metabolized in 1 h in human plasma. Two prodrugs (FK506-G or FK506-S) including FK506 showed an IC 50 of 336.6 μg/mL for FK506, 337.9 μg/mL for FK506-G, or 480.1 μg/mL for FK506-S against a conjunctive cell line, Clone 1-5c-4 cells. Taken together, FK506-S could be the most optimal prodrug for aqueous preparations based on preformulation data.

Redox-Responsive Hyaluronic Acid–Tacrolimus Conjugate: Synthesis, Characterization, and In Vitro Immunosuppressive Activity

“…The whole blood stability of the HA-ss-TAC conjugate was assessed in rat blood using a previously reported protocol. , Fresh whole blood was obtained from control Wistar rats in our institutional animal house. A stock solution of HA-ss-TAC conjugate was prepared in a solvent mixture of DMSO and water: (20:80, % v/v).…”

“…In the past decade, several alternative formulations such as self-microemulsifying drug delivery systems (SMEDDS), hydrogels, , liposomes, ethosomes, inclusion complexes, solid dispersions, micelles, , and nanoparticles have been utilized for improvement of TAC solubility. Along with this, many water-soluble prodrugs of TAC were synthesized with polymers such as polyethylene glycol (PEG), cyclodextrin, glucose, or sialic acid using a succinyl linker. − These prodrugs are often transformed into parent TAC through the hydrolysis of ester linkage by the esterase enzyme present in plasma and various tissues.…”

Late-stage diversification of bacterial natural products through biocatalysis

“…FK506 (tacrolimus, Figure 1Dii ) is an FDA-approved immunosuppressive drug originally produced by Streptomyces tsukubensis . It is currently used in the treatment of patients undergoing organ transplants, but also displays the potential to be used as an antifungal, neuroprotective and neuroregenerative agent ( Jung et al, 2021 ), and as therapy for conjunctivitis ( Na et al, 2016 ). However, in order to broaden its use to neuronal diseases, conjunctivitis and as an antifungal, its immunosuppressive activity must be abolished and its water solubility improved.…”

“…The same process could be applied to obtain the corresponding C-42 PEG-analog of rapamycin ( González-Sabín et al, 2011 ). The structure of the abovementioned derivatives was confirmed using ESI-MS. Na et al have also reported obtaining two water-soluble conjugates of FK506 via a spontaneous reaction of FK506 with a succinyl linker followed by an enzymatically catalyzed conjugation of glucose (affording FK506-G, Supplementary Table S1 , row xii) or amino carbohydrate sialic acid (FK506-S, Supplementary Table S1 , row xiii) by glucosyltransferase or sialyltransferase, respectively, and these conjugates were quantified by HPLC analysis ( Na et al, 2016 ).…”

Faktor-Faktor Yang Berhubungan Dengan Kemampuan Keluarga Dalam Pencegahan Kekambuhan Pasien Skizofrenia

“…Kekambuhan pada satu tahun terdiagnosa skizofrenia dialami oleh 60-70% pasien yang tidak mendapatkan pengobatan, 40% pasien hanya mendapat pengobatan, 15,7% pada pasien yang mendapat kombinasi terapi pengobatan dan mendapat dukungan dari tenaga kesehatan, keluarga dan masyarakat (Stuart, 2007). Prevalensi kekambuhan pada pasien skizofrenia itu sendiri berada dalam rentang 50-92% secara global (Waret and Mukherjee, 2014).…”